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Sildenafil Improves Alveolar Growth and Pulmonary Hypertension in Hyperoxia-induced Lung Injury

Vascular Biology Research Group, Department of Pediatrics, Division of Neonatology, and Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada

Correspondence and requests for reprints should be addressed to Bernard Thébaud, M.D., Ph.D., Department of Pediatrics-Division of Neonatology, Vascular Biology Group, HMRC 407, University of Alberta, Edmonton, AB, T6G 2S2 Canada. E-mail: bthebaud{at}ualberta.ca

Rationale: Bronchopulmonary dysplasia (BPD), the chronic lung disease of preterm infants, and pulmonary emphysema, both significant global health problems, are characterized by an arrest in alveolar growth/loss of alveoli structures. Mechanisms that inhibit distal lung growth are poorly understood, but recent studies suggest that impaired vascular endothelial growth factor signaling and reduced nitric oxide (NO) production decreases alveolar and vessel growth in the developing lung, features observed in experimental oxygen-induced BPD. NO exerts its biological activity by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production. Objectives: Because cGMP is inactivated by phosphodiesterase (PDE) enzymes, we hypothesized that the cGMP-specific PDE5 inhibitor sildenafil would promote angiogenesis and attenuate oxygen-induced lung injury in newborn rats. Methods, Measurements, and Main Results: In vitro, sildenafil (10^–4 M) increased endothelial capillary network formation of human pulmonary endothelial cells exposed to hyperoxia. In vivo, rat pups were randomly exposed from birth to normoxia, hyperoxia (95% O₂, BPD model), and hyperoxia+sildenafil (100 mg/kg/day subcutaneously). Rat pups exposed to hyperoxia showed fewer and enlarged air spaces as well as decreased capillary density, mimicking pathologic features seen in human BPD. These structural anomalies were associated with echographic (decreased pulmonary acceleration time) and structural (right ventricular hypertrophy and increased medial wall thickness) signs of pulmonary hypertension. Sildenafil preserved alveolar growth and lung angiogenesis, and decreased pulmonary vascular resistance, right ventricular hypertrophy and medial wall thickness. Conclusions: Our findings suggest a role for the NO/cGMP pathway during alveolar development. Sildenafil may have therapeutic potential in diseases associated with impaired alveolar structures.

Key Words: alveoli • angiogenesis • cGMP • nitric oxide • oxygen

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